1. Field of the Invention
The field of the invention is pentafluorobenzenesulfonamide derivatives and analogs and their use as pharmacologically active agents.
2. Background
A number of human diseases stem from processes of uncontrolled or abnormal cellular proliferation. Most prevalent among these is cancer, a generic name for a wide range of cellular malignancies characterized by unregulated growth, lack of differentiation, and the ability to invade local tissues and metastasize. These neoplastic malignancies affect, with various degrees of prevalence, every tissue and organ in the body. A multitude of therapeutic agents have been developed over the past few decades for the treatment of various types of cancer. The most commonly used types of anticancer agents include: DNA-alkylating agents (e.g., cyclophosphamide, ifosfamide), antimetabolites (e.g., methotrexate, a folate antagonist, and 5-fluorouracil, a pyrimidine antagonist), microtubule disruptors (e.g., vincristine, vinblastine, paclitaxel), DNA intercalators (e.g., doxorubicin, daunomycin, cisplatin), and hormone therapy (e.g., tamoxifen, flutamide). The ideal antineoplastic drug would kill cancer cells selectively, with a wide therapeutic index relative to its toxicity towards non-malignant cells. It would also retain its efficacy against malignant cells even after prolonged exposure to the drug. Unfortunately, none of the current chemotherapies possess an ideal profile. Most possess very narrow therapeutic indexes, and in practically every instance cancerous cells exposed to slightly sublethal concentrations, of a chemotherapeutic agent will develop resistance to such an agent, and quite often cross-resistance to several other antineoplastic agents.
Psoriasis, a common chronic skin disease characterized by the presence of dry scales and plaques, is generally thought to be the result of abnormal cell proliferation. The disease results from hyperproliferation of the epidermis and incomplete differentiation of keratinocytes. Psoriasis often involves the scalp, elbows, knees, back, buttocks, nails, eyebrows, and genital regions, and may range in severity from mild to extremely debilitating, resulting in psoriatic arthritis, pustular psoriasis, and exfoliative psoriatic dermatitis. No therapeutic cure exists for psoriasis. Milder cases are often treated with topical corticosteroids, but more severe cases may be treated with antiproliferative agents, such as the antimetabolite methotrexate, the DNA synthesis inhibitor hydroxyurea, and the microtubule disrupter colchicine.
Other diseases associated with an abnormally high level of cellular proliferation include restenosis, where vascular smooth muscle cells are involved, inflammatory disease states, where endothelial cells, inflammatory cells and glomerular cells are involved, myocardial infarction, where heart muscle cells are involved, glomerular nephritis, where kidney cells are involved, transplant rejection, where endothelial cells are involved, infectious diseases such as HIV infection and malaria, where certain immune cells and/or other infected cells are involved, and the like. Infectious and parasitic agents per se (e.g. bacteria, trypanosomes, fungi, etc) are also subject to selective proliferative control using the subject compositions and compounds.
Accordingly, it is one object of the present invention to provide compounds which directly or indirectly are toxic to actively dividing cells and are useful in the treatment of cancer, viral and bacterial infections, vascular restenosis, inflammatory diseases, autoimmune diseases, and psoriasis.
A further object of the present invention is to provide therapeutic compositions for treating said conditions.
Still further objects are to provide methods for killing actively proliferating cells, such as cancerous, bacterial, or epithelial cells, and treating all types of cancers, infections, inflammatory, and generally proliferative conditions. A further object is to provide methods for treating other medical conditions characterized by the presence of rapidly proliferating cells, such as psoriasis and other skin disorders.
Other objects, features and advantages will become apparent to those skilled in the art from the following description and claims.
The invention provides methods and compositions relating to novel pentafluorophenylsulfonamide derivatives and analogs and their use as pharmacologically active agents. The compositions find particular use as pharmacological agents in the treatment of disease states, particularly cancer, bacterial infections and psoriasis, or as lead compounds for the development of such agents.
In one embodiment, the invention provides for the pharmaceutical use of compounds of the general formula I and for pharmaceutically acceptable compositions of compounds of formula I: 
or a physiologically acceptable salt thereof, wherein:
Y is xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94;
Z is xe2x80x94NR1R2 or xe2x80x94OR3, where R1 and R2 are independently selected from
hydrogen,
substituted or unsubstituted (C1-C10)alkyl,
substituted or unsubstituted (C1-C10)alkoxy,
substituted or unsubstituted (C3-C6)alkenyl,
substituted or unsubstituted (C2-C6)heteroalkyl,
substituted or unsubstituted (C3-C6)heteroalkenyl,
substituted or unsubstituted (C3-C6)alkynyl,
substituted or unsubstituted (C3-C8)cycloalkyl,
substituted or unsubstituted (C5-C7)cycloalkenyl,
substituted or unsubstituted (C5-C7)cycloalkadienyl,
substituted or unsubstituted aryl,
substituted or unsubstituted aryloxy,
substituted or unsubstituted aryl-(C3-C8)cycloalkyl,
substituted or unsubstituted aryl-(C5-C7)cycloalkenyl,
substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl,
substituted or unsubstituted aryl-(C1-C4)alkyl,
substituted or unsubstituted aryl-(C1-C4)alkoxy,
substituted or unsubstituted aryl-(C1-C4)heteroalkyl,
substituted or unsubstituted aryl-(C3-C6)alkenyl,
substituted or unsubstituted aryloxy-(C1-C4)alkyl,
substituted or unsubstituted aryloxy-(C2-C4)heteroalkyl,
substituted or unsubstituted heteroaryl,
substituted or unsubstituted heteroaryloxy,
substituted or unsubstituted heteroaryl-(C1-C4)alkyl,
substituted or unsubstituted heteroaryl-(C1-C4)alkoxy,
substituted or unsubstituted heteroaryl-(C1-C4)heteroalkyl,
substituted or unsubstituted heteroaryl-(C3-C6)alkenyl,
substituted or unsubstituted heteroaryloxy-(C1-C4)alkyl, and
substituted or unsubstituted heteroaryloxy-(C2-C4)heteroalkyl,
wherein R1 and R2 may be connected by a linking group E to give a substituent of the formula 
wherein E represents a bond, (C1-C4) alkylene, or (C1-C4) heteroalkylene, and the ring formed by R1, E, R2 and the nitrogen contains no more than 8 atoms, or preferably the R1 and R2 may be covalently joined in a moiety that forms a 5- or 6-membered heterocyclic ring with the nitrogen atom of NR1R2;
and where R3 is a substituted or unsubstituted aryl or heteroaryl group.
Substituents for the alkyl, alkoxy, alkenyl, heteroalkyl, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and cycloalkadienyl radicals are selected independently from
xe2x80x94H
xe2x80x94OH
xe2x80x94Oxe2x80x94(C1-C10)alkyl
xe2x95x90O
xe2x80x94NH2 
xe2x80x94NHxe2x80x94(C1-C10)alkyl
xe2x80x94N[(C1-C10)alkyl]2 
xe2x80x94SH
xe2x80x94Sxe2x80x94(C1-C10)alkyl
-halo
xe2x80x94Si[(C1-C10)alkyl]3 
in a number ranging from zero to (2N+1), where N is the total number of carbon atoms in such radical.
Substituents for the aryl and heteroaryl groups are selected independently from
-halo
xe2x80x94OH
Oxe2x80x94Rxe2x80x2
xe2x80x94Oxe2x80x94C(O)xe2x80x94Rxe2x80x2
xe2x80x94NH2 
xe2x80x94NHRxe2x80x2
xe2x80x94NRxe2x80x2Rxe2x80x3
xe2x80x94SH
xe2x80x94SRxe2x80x2
xe2x80x94Rxe2x80x2
xe2x80x94CN
xe2x80x94NO2 
xe2x80x94CO2H
xe2x80x94CO2xe2x80x94Rxe2x80x2
xe2x80x94CONH2 
xe2x80x94CONHxe2x80x94Rxe2x80x2
xe2x80x94CONRxe2x80x2Rxe2x80x3
xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94Rxe2x80x2
xe2x80x94Oxe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x3
xe2x80x94NHxe2x80x94C(O)xe2x80x94Rxe2x80x2
xe2x80x94NRxe2x80x3xe2x80x94C(O)xe2x80x94Rxe2x80x2
xe2x80x94NHxe2x80x94C(O)xe2x80x94ORxe2x80x2
xe2x80x94NRxe2x80x3xe2x80x94C(O)xe2x80x94Rxe2x80x2
xe2x80x94NHxe2x80x94C(NH2)xe2x95x90NH
xe2x80x94NRxe2x80x2xe2x80x94C(NH2)xe2x95x90NH
xe2x80x94NHxe2x80x94C(NH2)xe2x95x90NRxe2x80x2
xe2x80x94S(O)xe2x80x94Rxe2x80x2
xe2x80x94S(O)2xe2x80x94Rxe2x80x2
xe2x80x94S(O)2xe2x80x94NHxe2x80x94Rxe2x80x2
xe2x80x94S(O)2xe2x80x94NRxe2x80x2Rxe2x80x3
xe2x80x94N3 
xe2x80x94CH(Ph)2 
substituted or unsubstituted aryloxy
substituted or unsubstituted arylamino
substituted or unsubstituted heteroarylamino
substituted or unsubstituted heteroaryloxy
substituted or unsubstituted aryl-(C1-C4)alkoxy,
substituted or unsubstituted heteroaryl-(C1-C4)alkoxy,
perfluoro(C1-C4)alkoxy, and
perfluoro(C 1 -C4)alkyl,
in a number ranging from zero to the total number of open valences on the aromatic ring system;
and where Rxe2x80x2 and Rxe2x80x3 are independently selected from:
substituted or unsubstituted (C1-C10)alkyl,
substituted or unsubstituted (C1-C10)heteroalkyl,
substituted or unsubstituted (C2-C6)alkenyl,
substituted or unsubstituted (C2-C6)heteroalkenyl,
substituted or unsubstituted (C2-C6)alkynyl,
substituted or unsubstituted (C3-C8)cycloalkyl,
substituted or unsubstituted (C3-C8)heterocycloalkyl,
substituted or unsubstituted (C5-C6)cycloalkenyl,
substituted or unsubstituted (C5-C6)cycloalkadienyl,
substituted or unsubstituted aryl,
substituted or unsubstituted aryl-(C1-C4)alkyl,
substituted or unsubstituted aryl-(C1-C4)heteroalkyl,
substituted or unsubstituted aryl-(C2-C6)alkenyl,
substituted or unsubstituted aryloxy-(C1-C4)alkyl,
substituted or unsubstituted aryloxy-(C1-C4)heteroalkyl,
substituted or unsubstituted heteroaryl,
substituted or unsubstituted heteroaryl-(C1-C4)alkyl,
substituted or unsubstituted heteroaryl-(C1-C4)heteroalkyl,
substituted or unsubstituted heteroaryl-(C2-C6)alkenyl,
substituted or unsubstituted heteroaryloxy-(C1-C4)alkyl, and
substituted or unsubstituted heteroaryloxy-(C1-C4)heteroalkyl.
Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula xe2x80x94Txe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Uxe2x80x94, wherein T and U are independently selected from N, O, and C, and n=0-2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula xe2x80x94Axe2x80x94(CH2)pxe2x88x92Bxe2x80x94, wherein A and B are independently selected from C, O, N, S, SO, SO2, and SO2NRxe2x80x2, and p=1-3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula xe2x80x94(CH2)qxe2x80x94Xxe2x80x94(CH2)rxe2x80x94, where q and r are independently 1-3, and X is selected from O, N, S, SO, SO2 and SO2NRxe2x80x2. The substituent Rxe2x80x2 in SO2NRxe2x80x2 is selected from hydrogen or (C1-C6)alkyl.
In another embodiment, the invention provides novel methods for the use of pharmaceutical compositions containing compounds of the foregoing description of the general formula I. The invention provides novel methods for treating pathology such as cancer, bacterial infections and psoriasis, including administering to a patient an effective formulation of one or more of the subject compositions.
In another embodiment, the invention provides chemically-stable, pharmacologically active compounds of general formula I: 
or a pharmaceutically acceptable salt thereof, wherein:
Y is xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O2)xe2x80x94; and
Z is NR1R2, wherein R2 is an optionally substituted aryl or heteroaryl group, and R1 is selected from:
hydrogen,
substituted or unsubstituted (C1-C10)alkyl,
substituted or unsubstituted (C1-C10)alkoxy,
substituted or unsubstituted (C3-C6)alkenyl,
substituted or unsubstituted (C2-C6)heteroalkyl,
substituted or unsubstituted (C3-C6)heteroalkenyl,
substituted or unsubstituted (C3-C6)alkynyl,
substituted or unsubstituted (C3-C8)cycloalkyl,
substituted or unsubstituted (C5-C7)cycloalkenyl,
substituted or unsubstituted (C5-C7)cycloalkadienyl,
substituted or unsubstituted aryl,
substituted or unsubstituted aryloxy,
substituted or unsubstituted aryl-(C3-C8)cycloalkyl,
substituted or unsubstituted aryl-(C5-C7)cycloalkenyl,
substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl,
substituted or unsubstituted aryl-(C1-C4)alkyl,
substituted or unsubstituted aryl-(C1-C4)alkoxy,
substituted or unsubstituted aryl-(C3-C4)heteroalkyl,
substituted or unsubstituted aryl-(C3-C6)alkenyl,
substituted or unsubstituted aryloxy-(C3-C4)alkyl,
substituted or unsubstituted aryloxy-(C2-C4)heteroalkyl,
substituted or unsubstituted heteroaryl,
substituted or unsubstituted heteroaryloxy,
substituted or unsubstituted heteroaryl-(C1-C4)alkyl,
substituted or unsubstituted heteroaryl-(C1-C4)alkoxy,
substituted or unsubstituted heteroaryl-(C1-C4)heteroalkyl,
substituted or unsubstituted heteroaryl-(C3-C6)alkenyl,
substituted or unsubstituted heteroaryloxy-(C1-C4)alkyl, and
substituted or unsubstituted heteroaryloxy-(C2-C4)heteroalkyl,
wherein R1 and R2 may be connected by a linking group E to give a substituent of the formula 
wherein E represents a bond, (C1-C4) alkylene, or (C1-C4) heteroalkylene, and the ring formed by R1, E, R2 and the nitrogen contains no more than 8 atoms, or preferably the R1 and R2 may be covalently joined in a moiety that forms a 5- or 6-membered heterocyclic ring with the nitrogen atom of NR1R2;
provided that:
in the case that Y is xe2x80x94S(O2)xe2x80x94, and R1 is hydrogen or methyl, then R2 is substituted phenyl or heteroaryl group;
in the case that Y is xe2x80x94S(O2)xe2x80x94 and R2 is a ring system chosen from 1-naphthyl, 5-quinolyl, or 4-pyridyl, then either R1 is not hydrogen or R2 is substituted by at least one substituent that is not hydrogen;
in the case that Y is xe2x80x94S(O2)xe2x80x94, R2 is phenyl, and R1 is a propylene unit attaching the nitrogen of xe2x80x94NR1R2xe2x80x94 to the 2-position of the phenyl ring in relation to the sulfonamido group to form a 1,2,3,4-tetrahydroquinoline system, one or more of the remaining valences on the bicyclic system so formed is substituted with at least one substituent that is not hydrogen;
in the case that Y is xe2x80x94S(O2)xe2x80x94 and R2 is phenyl substituted with 3-(1-hydroxyethyl), 3-dimethylamino, 4-dimethylamino, 4-phenyl, 3-hydroxy, 3-hydroxy-4-diethylaminomethyl, 3,4-methylenedioxy, 3,4-ethylenedioxy, 2-(1-pyrrolyl), or 2-methoxy-4-(1-morpholino), then either R1 is not hydrogen or when R1 is hydrogen, one or more of the remaining valences on the phenyl ring of R2 is substituted with a substituent that is not hydrogen;
in the case that Y is xe2x80x94S(O2)xe2x80x94 and R2 is 2-methylbenzothiazol-5-yl, 6-hydroxy-4-methyl-pyrimidin-2-yl, 3-carbomethoxypyrazin-2-yl, 5-carbomethoxypyrazin-2-yl, 4-carboethoxy-1-phenylpyrazol-5-yl, 3-methylpyrazol-5-yl, 4-chloro-2-methylthiopyrimidin-6-yl, 2-trifluoromethyl-1,3,4-thiadiazol-5-yl, 5,6,7,8-tetrahydro-2-naphthyl, 4-methylthiazol-2-yl, 6,7-dihydroindan-5-yl, 7-chloro-5-methyl-1,8-naphthyridin-2-yl, 5,7-dimethyl-1,8-naphthyridin-2-yl, or 3-cyanopyrazol-4-yl, R1 is a group other than hydrogen.
The term xe2x80x9calkylxe2x80x9d by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon radical, including di- and multi-radicals, having the number of carbon atoms designated (i.e. C1-C10 means one to ten carbons) and includes straight or branched chain groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of n-pentyl, n-hexyl, 2-methylpentyl, 1,5-dimethylhexyl, 1-methyl-4-isopropylhexyl and the like. The term xe2x80x9calkylenexe2x80x9d by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by xe2x80x94CH2CH2CH2CH2xe2x80x94. A xe2x80x9clower alkylxe2x80x9d is a shorter chain alkyl, generally having six or fewer carbon atoms.
The term xe2x80x9cheteroalkylxe2x80x9d by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain radical consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94OH, xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94N(CH3)xe2x80x94CH3, xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94S(O)xe2x80x94CH3, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94CH3, and xe2x80x94CH2xe2x80x94CH2xe2x80x94S(O)2xe2x80x94CH3. Up to two heteroatoms may be consecutive, such as, for example, xe2x80x94CH2xe2x80x94NHxe2x80x94OCH3. The term xe2x80x9cheteroalkylenexe2x80x9d by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94 and xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94.
The terms xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9cheterocycloalkylxe2x80x9d, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of xe2x80x9calkylxe2x80x9d and xe2x80x9cheteroalkylxe2x80x9d, respectively. Examples of cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl, and the like. Examples of heterocycloalkyl include 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
The term xe2x80x9calkenylxe2x80x9d employed alone or in combination with other terms, means, unless otherwise stated, a stable straight chain or branched monounsaturated or diunsaturated hydrocarbon group having the stated number of carbon atoms. Examples include vinyl, propenyl (allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and the higher homologs and isomers. A divalent radical derived from an alkene is exemplified by xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94.
The term xe2x80x9cheteroalkenylxe2x80x9d by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated or diunsaturated hydrocarbon radical consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quarternized. Up to two heteroatoms may be placed consecutively. Examples include xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94CH3, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94OH, xe2x80x94CH2xe2x80x94CHxe2x95x90Nxe2x80x94OCH3, xe2x80x94CHxe2x95x90CHxe2x80x94N(CH3)xe2x80x94CH3, and xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94SH.
The term xe2x80x9calkynylxe2x80x9d employed alone or in combination with other terms, means, unless otherwise stated, a stable straight chain or branched hydrocarbon group having the stated number of carbon atoms, and containing one or two carbon-carbon triple bonds, such as ethynyl, 1- and 3-propynyl, 4-but-1-ynyl, and the higher homologs and isomers.
The term xe2x80x9calkoxyxe2x80x9d employed alone or in combination with other terms, means, unless otherwise stated, an alkyl group, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy and the higher homologs and isomers.
The terms xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
The term xe2x80x9carylxe2x80x9d employed alone or in combination with other terms, means, unless otherwise stated, a phenyl, 1-naphthyl, or 2-naphthyl group. The maximal number of substituents allowed on each one of these ring systems is five, seven, and seven, respectively. Substituents are selected from the group of acceptable substituents listed above.
The term xe2x80x9cheteroarylxe2x80x9d by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted, stable, mono- or bicyclic heterocyclic aromatic ring system which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. The heterocyclic system may be attached, unless otherwise stated at any heteroatom or carbon atom which affords a stable structure. The heterocyclic system may be substituted or unsubstituted with one to four substituents independently selected from the list of acceptable aromatic substituents listed above. Examples of such heterocycles include 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.
Pharmaceutically acceptable salts of the compounds of Formula I include salts of these compounds with relatively nontoxic acids or bases, depending on the particular substituents found on specific compounds of Formula I. When compounds of Formula I contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of compound I with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of Formula I contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of compound I with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like gluconic or galactunoric acids and the like (see, for example, Berge, S. M., et al, xe2x80x9cPharmaceutical Saltsxe2x80x9d, Journal of Pharmaceutical Science, Vol. 66, pages 1-19 (1977)). Certain specific compounds of Formula I contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The free base form may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
Certain compounds of the present invention possess asymmetric carbon atoms (optical centers); the racemates, diastereomers, and individual isomers are all intended to be encompassed within the scope of the present invention.
The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
In various preferred embodiments of the pharmaceutical compositions of compounds of formula I, Y is S(O2) and Z is NR1R2, wherein R1 is hydrogen or methyl, and R2 is a substituted phenyl, preferably mono-, di-, or trisubstituted as follows. In one group of preferred compounds, Y is S(O2) and Z is NR1R2, wherein R1 is hydrogen or methyl, and R2 is a phenyl group, preferably substituted in the para position by one of the following groups: hydroxy, amino, (C1-C10)alkoxy, (C1-C10)alkyl, (C1-C10)alkylamino, and [di(C1-C10)alkyl]amino, with up to four additional substituents independently chosen from hydrogen, halogen, (C1-C10)alkoxy, (C1-C10)alkyl, and [di(C1-C10)alkyl]amino. Also preferred are compounds of formula I where there is no linking group E between R1 and R2.
Illustrative examples of pharmaceutical compositions and compounds of the subject pharmaceutical methods include:
2-Fluoro-1-methoxy-4-pentafluorophenylsulfinamidobenzene;
4-Dimethylamino-1-pentafluorophenylsulfinamidobenzene;
4-Methyl-6-methoxy-2-pentafluorophenylsulfonamidopyrimidine;
4,6-Dimethoxy-2-pentafluorophenylsulfonamidopyrimidine;
2-Pentafluorophenylsulfonamidothiophene;
3-Pentafluorophenylsulfonamidothiophene;
3-Pentafluorophenylsulfonamidopyridine;
4-Pentafluorophenylsulfonamidopyridine;
4-(N,N,-Dimethylamino)-1-(N-ethylpentafluorophenylsulfonamido)-benzene;
4-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;
3-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;
2-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;
4-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;
3-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;
2-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;
2-Methoxy-1,3-difluoro-5-pentafluorophenylsulfonamidobenzene;
4-Cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;
3-Fluoro-4-cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;
3-Hydroxy-4-cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;
1-Hydroxy-2,3-methylenedioxy-5-pentafluorophenylsulfonamidobenzene;
1-Hydroxy-2,3-ethylenedioxy-5-pentafluorophenylsulfonamidobenzene;
1-Hydroxy-2,3-carbodioxy-5-pentafluorophenylsulfonamidobenzene;
1,3-Dihydroxy-2-ethoxy-5-pentafluorophenylsulfonamidobenzene;
1-Pentafluorophenylsulfonylindole;
1-Pentafluorophenylsulfonyl(2,3-dihydro)indole;
1-Pentafluorophenylsulfonyl(1,2-dihydro)quinoline;
1-Pentafluorophenylsulfonyl(1,2,3,4-tetrahydro)quinoline;
3,4-Difluoro-1-pentafluorophenylsulfonamidobenzene;
4-Trifluoromethoxy-1-pentafluorophenylsulfonamidobenzene;
2-Chloro-5-pentafluorophenylsulfonamidopyridine;
2-Hydroxy-1-methoxy-4-[N-5-hydroxypent-1-yl)pentafluorophenyl-sulfonamido]benzene;
4-(1,1-Dimethyl)ethoxy-1-pentafluorophenylsulfonamidobenzene;
1-Bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene;
2-Bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene;
1-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene;
3-Chloro-1-pentafluorophenylsulfonamidobenzene;
4-Chloro-1-pentafluorophenylsulfonamidobenzene;
3-Nitro-1-pentafluorophenylsulfonamidobenzene;
4-Methoxy-1-pentafluorophenylsulfonamido-3-(trifluoromethyl)benzene;
4-Methoxy-1-[N-(2-propenyl)pentafluorophenylsulfonamido]benzene;
1-(N-(3-Butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene;
4-Methoxy-1-(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene;
1-[N-(2,3-Dihydroxypropyl)pentafluorophenylsulfonamido]-4-methoxy-benzene;
1-(N-(3,4-Dihydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene;
1-(N-(4,5-Dihydroxypentyl)pentafluorophenylsulfonamido)-4-methoxybenzene;
1-(N-(4-hydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene;
4-Methoxy-1-(N-(5-hydroxypentyl)pentafluorophenylsulfonamido)-benzene;
3-Amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene;
4-Butoxy-1-pentafluorophenylsulfonamidobenzene;
1-Pentafluorophenylsulfonamido-4-phenoxybenzene;
6-Pentafluorophenylsulfonamidoquinoline;
2,3-Dihydro-5-pentafluorophenylsulfonamidoindole;
5-Pentafluorophenylsulfonamido benzo[a]thiophene;
5-Pentafluorophenylsulfonamidobenzo[a]furan;
3-Hydroxy-4-(1-propenyl)-1-pentafluorophenylsulfonamidobenzene;
4-Benzyloxy-1-pentafluorophenylsulfonamidobenzene;
4-Methylmercapto-1-pentafluorophenylsulfonamidobenzene;
2-Methoxy-1-pentafluorophenylsulfonamidobenzene;
4-Allyloxy-1-pentafluorophenylsulfonamidobenzene;
1-Pentafluorophenylsulfonamido-4-propoxybenzene;
4-(1-Methyl)ethoxy-1-pentafluorophenylsulfonamidobenzene;
1,2-Methylenedioxy-4-pentafluorophenylsulfonamidobenzene;
1,2-Dimethoxy-4-pentafluorophenylsulfonamidobenzene;
4-(N,N-Diethylamino)-1-pentafluorophenylsulfonamidobenzene;
4-Amino-1-pentafluorophenylsulfonamidobenzene;
Pentafluorophenylsulfonamidobenzene;
5-Pentafluorophenylsulfonamidoindazole;
4-(N,N-Dimethylamino)-1-(N-methylpentafluorophenylsulfonamido)-benzene;
1,2-Dihydroxy-4-pentafluorophenylsulfonamidobenzene;
3,5-Dimethoxy-1-pentafluorophenylsulfonamidobenzene;
3-Ethoxy-1-pentafluorophenylsulfonamidobenzene;
7-Hydroxy-2-pentafluorophenylsulfonamidonaphthalene;
3-Phenoxy-1-pentafluorophenylsulfonamidobenzene;
4-(1-Morpholino)-1-pentafluorophenylsulfonamidobenzene;
5-Pentafluorophenylsulfonamido-1,2,3-trimethoxybenzene;
2-Hydroxy-1,3-methoxy-5-pentafluorophenylsulfonamidobenzene;
1,2-Dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene;
5-Pentafluorophenylsulfonamido-1,2,3-trihydroxybenzene;
3-Hydroxy-5-methoxy-1-pentafluorophenylsulfonamidobenzene;
3,5-Dihydroxy-1-pentafluorophenylsulfonamidobenzene;
2-Fluoro-1-methoxy-4-(N-methylpentafluorophenylsulfonamido)benzene;
4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene, hydrochloride;
2-Methoxy-5-pentafluorophenylsulfonamidopyridine; and
2-Anilino-3-pentafluorophenylsulfonamidopyridine.
Examples of the most preferred pharmaceutical compositions and compounds of the subject pharmaceutical methods include:
4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene;
3-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene;
1,2-Ethylenedioxy-4-pentafluorophenylsulfonamidobenzene;
2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt;
2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, potassium salt;
2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt;
2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, potassium salt;
4-Methoxy-1-pentafluorophenylsulfonamidobenzene;
3-Hydroxy-1-pentafluorophenylsulfonamidobenzene;
4-Hydroxy-1-pentafluorophenylsulfonamidobenzene;
1,2-Dimethyl-4-pentafluorophenylsulfonamidobenzene;
5-Pentafluorophenylsulfonamidoindole;
4-Ethoxy-1-pentafluorophenylsulfonamidobenzene;
3-Methoxy-1-pentafluorophenylsulfonamidobenzene;
2-Bromo-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
2-Chloro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
2-Bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene;
2-Bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene;
1-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene;
4-Chloro-1-pentafluorophenylsulfonamidobenzene; and
3-Amino4-methoxy-1-pentafluorophenylsulfonamidobenzene.
The invention provides for certain novel compounds of general Formula I that possess one or more valuable biological activities such as a pharmacologic, toxicologic, metabolic, etc. Exemplary compounds of this embodiment of the invention include:
2-Fluoro-1-methoxy-4-pentafluorophenylsulfinamidobenzene;
4-Dimethylamino-1-pentafluorophenylsulfinamidobenzene;
4-Methyl-6-methoxy-2-pentafluorophenylsulfonamidopyrimidine;
4,6-Dimethoxy-2-pentafluorophenylsulfonamidopyrimidine;
2-Pentafluorophenylsulfonamidothiophene;
3-Pentafluorophenylsulfonamidothiophene;
3-Pentafluorophenylsulfonamidopyridine;
4-Pentafluorophenylsulfonamidopyridine;
4-(N,N,-Dimethylamino)-1-(N-ethylpentafluorophenylsulfonamido)benzene;
4-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;
3-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;
2-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene;
4-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;
3-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;
2-Isopropoxy-1-pentafluorophenylsulfonamidobenzene;
2-Methoxy-1,3-difluoro-5-pentafluorophenylsulfonamidobenzene;
1-Hydroxy-2,3-methylenedioxy-5-pentafluorophenylsulfonamidobenzene;
1-Hydroxy-2,3-ethylenedioxy-5-pentafluorophenylsulfonamidobenzene;
1-Hydroxy-2,3-carbodioxy-5-pentafluorophenylsulfonamidobenzene;
1,3 -Dihydroxy-2-ethoxy-5-pentafluorophenylsulfonamidobenzene;
1-Pentafluorophenylsulfonylindole;
1-Pentafluorophenylsulfonyl(2,3-dihydro)indole;
1-Pentafluorophenylsulfonyl(1,2-dihydro)quinoline;
1-Pentafluorophenylsulfonyl(1,2,3,4-tetrahydro)quinoline;
3,4-Difluoro-1-pentafluorophenylsulfonamidobenzene;
4-Trifluoromethoxy-1-pentafluorophenylsulfonamidobenzene;
2-Chloro-5-Pentafluorophenylsulfonamidopyridine;
2-Hydroxy-1-methoxy-4-[N-5-hydroxypent-1-yl)pentafluorophenyl-sulfonamido]benzene;
4-(1,1-Dimethyl)ethoxy-1-pentafluorophenylsulfonamidobenzene;
1-Bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene;
2-Bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene;
1-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene;
3-Chloro-1-pentafluorophenylsulfonamidobenzene;
4-Chloro-1-pentafluorophenylsulfonamidobenzene;
3-Nitro-1-pentafluorophenylsulfonamidobenzene;
4-Methoxy-1-pentafluorophenylsulfonamido-3-(trifluoromethyl)benzene;
4-Methoxy-1-[N-(2-propenyl)pentafluorophenylsulfonamido]benzene;
1-(N-(3-Butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene;
4-Methoxy-1-(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene;
1-[N-(2,3-Dihydroxypropyl)pentafluorophenylsulfonamido]-4-methoxy-benzene;
1-(N-(3,4-Dihydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene;
1-(N-(4,5-Dihydroxypentyl)pentafluorophenylsulfonamido)-4-methoxybenzene;
1-(N-(4-hydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene;
4-Methoxy-1-(N-(5-hydroxypentyl)pentafluorophenylsulfonamido)-benzene;
3-Amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene;
4-Butoxy-1-pentafluorophenylsulfonamidobenzene;
1-Pentafluorophenylsulfonamido-4-phenoxybenzene;
4-Benzyloxy-1-pentafluorophenylsulfonamidobenzene;
4-Methylmercapto-1-pentafluorophenylsulfonamidobenzene;
2-Methoxy-1-pentafluorophenylsulfonamidobenzene;
4-Allyloxy-1-pentafluorophenylsulfonamidobenzene;
1-Pentafluorophenylsulfonamido-4-propoxybenzene;
4-(1-Methyl)ethoxy-1-pentafluorophenylsulfonamidobenzene;
1,2-Methylenedioxy-4-pentafluorophenylsulfonamidobenzene;
1,2-Dimethoxy-4-pentafluorophenylsulfonamidobenzene;
4-(N,N-Diethylamino)-1-pentafluorophenylsulfonamidobenzene;
4-Amino-1-pentafluorophenylsulfonamidobenzene;
Pentafluorophenylsulfonamidobenzene;
5-Pentafluorophenylsulfonamidoindazole;
4-(N,N-Dimethylamino)-1-(N-methylpentafluorophenylsulfonamido)-benzene;
1,2-Dihydroxy-4-pentafluorophenylsulfonamidobenzene;
3,5-Dimethoxy-1-pentafluorophenylsulfonamidobenzene;
3-Ethoxy-1-pentafluorophenylsulfonamidobenzene;
7-Hydroxy-2-pentafluorophenylsulfonamidonaphthalene;
3-Phenoxy-1-pentafluorophenylsulfonamidobenzene;
4-(1-Morpholino)-1-pentafluorophenylsulfonamidobenzene;
5-Pentafluorophenylsulfonamido-1,2,3-trimethoxybenzene;
2-Hydroxy-1,3-methoxy-5-pentafluorophenylsulfonamidobenzene;
1,2-Dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene;
5-Pentafluorophenylsulfonamido-1,2,3-trihydroxybenzene;
4-Cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;
3-Fluoro-4-cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;
6-Pentafluorophenylsulfonamidoquinoline;
2,3-Dihydro-5-pentafluorophenylsulfonamidoindole;
5-Pentafluorophenylsulfonamidobenzo[a]thiophene;
5-Pentafluorophenylsulfonamidobenzo[a]furan;
3-Hydroxy-4-(1-propenyl)-1-pentafluorophenylsulfonamidobenzene;
3-Hydroxy-5-methoxy-1-pentafluorophenylsulfonamidobenzene;
3,5-Dihydroxy-1-pentafluorophenylsulfonamidobenzene;
2-Fluoro-1-methoxy-4-(N-methylpentafluorophenylsulfonamido)benzene;
4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene, hydrochloride; and,
2-Anilino-3-pentafluorophenylsulfonamidopyridine.
Preferred compounds of this embodiment of the invention have specific pharmacological properties. Examples of the most preferred compounds of this embodiment of the invention include:
4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene;
3-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene;
1,2-Ethylenedioxy-4-pentafluorophenylsulfonamidobenzene;
2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt;
2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, potassium salt;
2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt;
2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, potassium salt;
4-Methoxy-4-pentafluorophenylsulfonamidobenzene;
3-Hydroxy-1-pentafluorophenylsulfonamidobenzene;
4-Hydroxy-1-pentafluorophenylsulfonamidobenzene;
1,2-Dimethyl-4-pentafluorophenylsulfonamidobenzene;
5-Pentafluorophenylsulfonamidoindole;
4-Ethoxy-1-pentafluorophenylsulfonamidobenzene;
3-Methoxy-1-pentafluorophenylsulfonamidobenzene;
2-Bromo-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
2-Chloro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
2-Bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene;
2-Bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene;
1-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene;
4-Chloro-1-pentafluorophenylsulfonamidobenzene; and
3-Amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene.
Synthesis 
The invention provides methods of making the subject compounds and compositions. In one general embodiment, the methods involve combining pentafluorophenylsulfonyl chloride with an amine having the general formula R1R2NH under conditions whereby the pentafluorophenylsulfonyl chloride and amine react to form the desired compound, and isolating the compound.
Compounds with the generic structure 1 or 3 (Scheme I) may be prepared by reacting the appropriate starting amine in a solvent such as tetrahydrofuran (THF), dimethylformamide (DMF), ether, toluene or benzene in the presence of a base such as pyridine, p-dimethylaminopyridine, triethylamine, sodium carbonate or potassium carbonate and pentafluorophenylsulfonyl chloride or pentafluorophenylsulfinyl chloride, respectively. Pyridine itself may also be used as the solvent. Preferred solvents are pyridine and DMF and preferred bases are pyridine, triethylamine, and potassium carbonate. This reaction can be carried out at a temperature range of 0xc2x0 C. to 100xc2x0 C., conveniently at ambient temperature.
Compounds of the generic structure 1 can also be obtained by treating the starting sulfonamide (Scheme II) with a base such as LDA, NaH, dimsyl salt, alkyl lithium, potassium carbonate, under an inert atmosphere such as argon or nitrogen, in a solvent such as benzene, toluene, DMF or THF with an alkylating group containing a leaving group such a Cl, Br, I, MsOxe2x80x94, TsOxe2x80x94, TFAOxe2x80x94, represented by E in Scheme II. A preferred solvent for this reaction is THF and the preferred base is lithium bis(trimethylsilyl)amide. This reaction can be carried out at a temperature range of 0xc2x0 C. to 100xc2x0 C., conveniently at ambient temperature.
Sulfonic esters (2) and sulfinic esters (4) may be prepared by reacting the appropriate starting phenol in a solvent such as THF, DMF, toluene or benzene in the presence of a base such as pyridine, triethylamine, sodium carbonate, potassium carbonate or 4-dimethylaminopyridine with pentafluorophenylsulfonyl chloride or pentafluorophenylsulfinyl chloride, respectively. Pyridine itself may also be used as the solvent. Preferred solvents are pyridine and DMF and preferred bases are sodium carbonate and potassium carbonate. This reaction can be carried out at a temperature range of 0xc2x0 C. to 100xc2x0 C., conveniently at ambient temperature.
Compounds of the general structure 5, in which Ar is an aromatic group and x is from one to three, can be obtained from the corresponding methyl ethers (Scheme III) by reaction with boron tribromide in a solvent of low polarity such as hexanes or CH2Cl2 under an inert atmosphere at a temperature ranging from xe2x88x9245xc2x0 to 30xc2x0 C. In a preferred embodiment, the reaction is carried out in CH2Cl2 at about 30xc2x0 C.
Occasionally, the substrates for the transformations shown in Schemes I-III may contain functional groups (for example, amino, hydroxy or carboxy) which are not immediately compatible with the conditions of the given reaction. In such cases, these groups may be protected with a suitable protective group, and this protective group removed subsequent to the transformation to give the original functionality using well know procedures such as those illustrated in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second Edition, John Wiley and Sons, Inc., 1991.
The compounds used as initial starting materials in this invention may be purchased from commercial sources or alternatively are readily synthesized by standard procedures which are well know to those of ordinary skill in the art.
Some of the compounds of formula I may exist as stereoisomers, and the invention includes all active stereoisomeric forms of these compounds. In the case of optically active isomers, such compounds may be obtained from corresponding optically active precursors using the procedures described above or by resolving racemic mixtures. The resolution may be carried out using various techniques such as chromatography, repeated recrystallization of derived asymmetric salts, or derivatization, which techniques are well known to those of ordinary skill in the art.
The compounds of formula I which are acidic or basic in nature can form a wide variety of salts with various inorganic and organic bases or acids, respectively. These salts must be pharmacologically acceptable for administration to mammals. Salts of the acidic compounds of this invention are readily prepared by treating the acid compound with an appropriate molar quantity of the chosen inorganic or organic base in an aqueous or suitable organic solvent and then evaporating the solvent to obtain the salt. Acid addition salts of the basic compounds of this invention can be obtained similarly by treatment with the desired inorganic or organic acid and subsequent solvent evaporation and isolation.
The compounds of the invention may be labeled in a variety of ways. For example, the compounds may be provided as radioactive isotopes; for example, tritium and the 14C-isotopes. Similarly, the compounds may be advantageously joined, covalently or noncovalently, to a wide variety of joined compounds which may provide pro-drugs or function as carriers, labels, adjuvents, coactivators, stabilizers, etc. Hence, compounds having the requisite structural limitations encompass such compounds joined directly or indirectly (e.g. through a linker molecule), to such joined compounds.
A wide variety of indications may be treated, either prophylactically or therapeutically, with the compounds and compositions of the present invention. For example, the subject compounds and compositions have been found to be effective modulators of cell proliferation. Limitation of cell growth is effected by contacting a target cell, in or ex vivo, with an effective amount of one or more of the subject compositions or compounds. Compounds may be assayed for their ability to modulate cellular proliferation using cell and animal models to evaluate cell growth inhibition and cytotoxicity, which models are known in the art, but are exemplified by the method of S. A. Ahmed et al. (1994) J. Immunol. Methods 170: 211-224, for determining the effects of compounds on cell growth.
Conditions amenable to treatment by the compounds and compositions of the present invention include any state of undesirable cell growth, including various neoplastic diseases, abnormal cellular proliferations and metastatic diseases, where any of a wide variety of cell types may be involved, including cancers such as Kaposi""s sarcoma, Wilms tumor, lymphoma, leukemia, myeloma, melanoma, breast, ovarian, lung, etc, and others such as cystic disease, cataracts, psoriasis, etc. Other conditions include restenosis, where vascular smooth muscle cells are involved, inflammatory disease states, where endothelial cells, inflammatory cells and glomerular cells are involved, myocardial infarction, where heart muscle cells are involved, glomerular nephritis, where kidney cells are involved, transplant rejection, where endothelial cells are involved, infectious diseases such as HIV infection and malaria, where certain immune cells and/or other infected cells are involved, and the like. Infectious and parasitic agents per se (e.g. trypanosomes, fungi, etc) are also subject to selective proliferative control using the subject compositions and compounds.
Many of the subject compounds have been shown to bind to the B-subunit of tubulin and interfere with normal tubulin function. Hence, the compounds provide agents for modulating cytoskeletal structure and/or function. Preferred compounds bind irreversibly or covalently, and hence provide enhanced application over prior art microtubule disruptors such as colchicine. The compositions may be advantageously combined and/or used in combination with other antiproliferative chemotherapeutic agents, different from the subject compounds (see Margolis et al. (1993) U.S. Pat. No. 5,262,409). Additional relevant literature includes: Woo et al. (1994) WO94/08041; Bouchard et al. (1996) WO96/13494; Bombardelli et al. (1996) WO96/11184; Bonura et al. (1992) WO92/15291.
Analysis
The subject compositions were demonstrated to have pharmacological activity in in vitro and in vivo assays, e.g. are capable of specifically modulating a cellular physiology to reduce an associated pathology or provide or enhance a prophylaxis. Preferred compounds display specific toxicity to various types of cells. Certain compounds and compositions of the present invention exert their cytotoxic effects by interacting with cellular tubulin. For certain preferred compounds and compositions of the present invention, that interaction is covalent and irreversible. For example, exposure of a wide variety of tissue and cell samples, e.g. human breast carcinoma MCF7 cells, to tritiated forms of these preferred compounds, e.g. Compound 7 (Example 72), results in the irreversible labeling of only one detectable cellular protein, which was found to be tubulin. This protein is a key component of microtubules, which constitute the cytoskeleton and also play critical roles in many other aspects of the cell""s physiology, including cell division. The labeling of tubulin by the subject preferred compounds is also shown to be dose-dependent. The site of covalent binding on tubulin is identified as Cysteine-239 on the xcex2-tubulin chain. The same Cys-239 residue is selectively covalently modified when present in a wide variety of Cys-239 containing xcex2-tubulin petides (e.g. Ser-234 to Met-267) provided in vitro or in vivo. One embodiment of these preferred compounds provides the binding mechanism shown in Scheme IV, namely, displacement of the para-fluorine atom by the thiol group of Cys-239. Consistent with the ability of these compounds to bind to xcex2-tubulin, treatment of a wide variety of cell and tissue types with various concentrations of the compounds resulted in widespread, irreversible disruption of the cytoskeleton of most cells.
As discribed inter alia in Luduena (1993) Mol Biol of the Cell 4, 445-457, tubulin defines a family of heterodimers of two polypeptides, designated xcex1 and xcex2. Moreover, animals express multiple forms (isotypes) of each xcex1 and xcex2 polypeptides from multiple a and xcex2 genes. Many xcex2 isotypes comprise a conserved cysteine, Cys-239 (of human xcex22 tubulin: because of upstream sequence variations, the absolute position of Cys-239 is subject to variation, though Cys-239 is readily identified by those in the art by its relative position (i.e. context within encompassing consensus sequence, e.g. at least 8, preferably 12, more preferably 16, most preferably 20 residue consensus peptide region of the isotype or fragment thereof, which region contains Cys-239). By selective binding to Cys-239 is meant that Cys-239 is preferentially bound relative to all other residues, including cysteins of the protein, by at least at least a factor of 2, preferably 10, more preferably 100, most preferably 1,000. In a particularly preferred embodiment, Cys-239 is substantially exclusively and preferably exclusive bound. By selective binding to or modification of tubulin is meant that tubulin is preferentially modified relative to all other proteins, by at least a factor of 2, preferably 10, more preferably 100, most preferably 1,000. In a particularly preferred embodiment, tubulin is substantially exclusively and preferably exclusive modified.
Compounds may be evaluated in vitro for their ability to inhibit cell growth, for example, as described in S. A. Ahmed et al. (1994) J. Immunol. Methods 170:211-224. In addition, established animal models to evaluate antiproliferative effects of compounds are known in the art. For example, several of the compounds disclosed herein are shown to inhibit the growth of human tumors, including MDR and taxol and/or vinblastine-resistant tumors, grafted into immunodeficient mice (using methodology similar to that reported by J. Rygaard and C. O. Povlsen (1969) Acta Pathol. Microbiol. Scand. 77:758-760, and reviewed by B. C. Giovanella and J. Fogh (1985) Adv. Cancer Res. 44:69-120.
Formulation and Administration
The invention provides methods of using the subject compounds and compositions to treat disease or provide medicinal prophylaxis, to slow down and/or reduce the growth of tumors, to treat bacterial infections, etc. These methods generally involve contacting cells with or administering to the host an effective amount of the subject compounds or pharmaceutically acceptable compositions.
The compositions and compounds of the invention and the pharmaceutically acceptable salts thereof can be administered in any effective way such as via oral, parenteral or topical routes. Generally, the compounds are administered in dosages ranging from about 2 mg up to about 2,000 mg per day, although variations will necessarily occur depending on the disease target, the patient, and the route of administration. Preferred dosages are administered orally in the range of about 0.05 mg/kg to about 20 mg/kg, more preferably in the range of about 0.05 mg/kg to about 2 mg/kg, most preferably in the range of about 0.05 mg/kg to about 0.2 mg per kg of body weight per day.
In one embodiment, the invention provides the subject compounds combined with a pharmaceutically acceptable excipient such as sterile saline or other medium, water, gelatin, an oil, etc. to form pharmaceutically acceptable compositions. The compositions and/or compounds may be administered alone or in combination with any convenient carrier, diluent, etc. and such administration may be provided in single or multiple dosages. Useful carriers include solid, semi-solid or liquid media including water and non-toxic organic solvents.
In another embodiment, the invention provides the subject compounds in the form of a pro-drug, which can be metabolically converted to the subject compound by the recipient host. A wide variety of pro-drug formulations are known in the art.
The compositions may be provided in any convenient form including tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, suppositories, etc. As such the compositions, in pharmaceutically acceptable dosage units or in bulk, may be incorporated into a wide variety of containers. For example, dosage units may be included in a variety of containers including capsules, pills, etc.
The compositions may be advantageously combined and/or used in combination with other antiproliferative therapeutic or prophylactic agents, different from the subject compounds. In many instances, administration in conjunction with the subject compositions enhances the efficacy of such agents. Exemplary antiproliferative agents include cyclophosphamide, methotrexate, adriamycin, cisplatin, daunomycin, vincristine, vinblastine, vinarelbine, paclitaxel, docetaxel, tamoxifen, flutamide, hydroxyurea, and mixtures thereof.
The compounds and compositions also find use in a variety of in vitro and in vivo assays, including diagnostic assays. In certain assays and in in vivo distribution studies, it is desirable to used labeled versions of the subject compounds and compositions, e.g. radioligand displacement assays. Accordingly, the invention provides the subject compounds and compositions comprising a detectable label, which may be spectroscopic (e.g. fluorescent), radioactive, etc.
The following examples are offered by way of illustration and not by way of limitation.